There are a limited number of options for clinical surgeons who are faced with reconstructing bone defects that result from congenital anomalies, trauma, infection, and oncologic resection. Current grafting techniques and materials each have their own limitations and drawbacks. For this reason, we aim to create improved bone grafting materials that will act as scaffolds to recruit cells from surrounding tissues and promote natural bone regeneration processes. Using a versatile and robust thiol-ene polymerization scheme developed in the Anseth and Bowman laboratories, we are able to create 3-dimensional matrices containing simple cell adhesion mimics and enzymatically-degradable linkages. As a result, these materials support cellular infiltration and are replaced as new tissue is formed by the body. The research proposed herein will aim to engineer these grafting materials for bone regeneration purposes, first by increasing the ability of cells from the body to migrate into these materials, and then by incorporating signals that tell the invading cells to become bone. Three specific aims are outlined: Aim I: Identify biological epitopes and functionalities that influence the rate of migration of cells into and through thiol-ene polymer scaffolds. Aim II: Develop thiol-ene polymer scaffolds that promote osteogenic differentiation and deposition of a mineralized matrix. Aim III: Demonstrate the ability of injectable polymer scaffolds developed in Aims I & II to promote bone regeneration in vivo. Successful completion of these Aims should significantly advance our understanding of how to design synthetic polymer scaffolds to enhance natural bone regeneration processes, and this material platform should be readily tailored for applications towards regenerating tissues beyond bone, as well as providing specific advantages for future directions in the design of cell delivery vehicles.